[¹⁸F]-Organotrifluoroborates as Radioprosthetic Groups for PET Imaging: From Design Principles to Preclinical Applications

Abstract

Positron emission tomography (PET) is revolutionizing our ability to visualize in vivo targets for target validation and personalized medicine. Of several classes of imaging agents, peptides afford high affinity and high specificity to distinguish pathologically distinct cell types by the presence of specific molecular targets. Of various available PET isotopes, [(18)F]-fluoride ion is preferred because of its excellent nuclear properties and on-demand production in hospitals at Curie levels. However, the short half-life of (18)F and its lack of reactivity in water continue to challenge peptide labeling. Hence, peptides are often conjugated to a metal chelator for late-stage, one-step labeling. Yet radiometals, while effective, are neither as desirable nor as available as [(18)F]-fluoride ion. Despite considerable past success in identifying semifeasible radiosyntheses, significant challenges continue to confound tracer development. These interrelated challenges relate to (1) isotope/prosthetic choice; (2) bioconjugation for high affinity; (3) high radiochemical yields, (4) specific activities of >1 Ci/μmol to meet FDA microdose requirements; and (5) rapid clearance and in vivo stability. These enduring challenges have been extensively highlighted, while a single-step, operationally simple, and generally applicable means of labeling a peptide with [(18)F]-fluoride ion in good yield and high specific activity has eluded radiochemists and nuclear medicine practitioners for decades. Radiosynthetic ease is of primordial importance since multistep labeling reactions challenge clinical tracer production. In the past decade, as we sought to meet this challenge, appreciation of reactions with aqueous fluoride led us to consider organotrifluoroborate (RBF3(-)) synthesis as a means of rapid aqueous peptide labeling. We have applied principles of mechanistic chemistry, knowledge of chemical reactivity, and synthetic chemistry to design stable RBF3(-)s. Over the past 10 years, we have developed several new [(18)F]-RBF3(-) radioprosthetic groups, all of which guarantee radiosynthetic ease while in most cases providing high tumor:nontumor (T:NT) ratios and moderate-to-high tumor uptake. Although others have developed methods for labeling of peptides with [(18)F]-silylfluorides or [(18)F]-Al-NOTA chelates, this Account focuses on the synthesis of [(18)F]-organotrifluoroborates. In this Account, I detail mechanistic, kinetic, thermodynamic, synthetic, and radiosynthetic approaches that enabled the translation of fundamental principles regarding the chemistry of RBF3(-)s into a tantalizingly close realization of a clinical application of an [(18)F]-organotrifluoroborate-peptide conjugate for imaging of neuroendocrine tumors and the generalization of this method for labeling of several other peptides.

Facile room temperature synthesis of fluorine-18 labeled fluoronicotinic acid-2,3,5,6-tetrafluorophenyl ester without azeotropic drying of fluorine-18

“…Although there are a few reports of direct fluorine-18 labeling of peptide,[30-33] fluorine-18 labeling of proteins are mostly done by an indirect approach using different fluorine-18 labeled small molecules. [34, 35] Therefore it is important to have a convenient synthetic method to prepare a labeled synthon in high yield in a short time.…”

A Conjugate of Pentamethine Cyanine and 18F as a Positron Emission Tomography/Near-Infrared Fluorescence Probe for Multimodality Tumor Imaging

“…This reagent could be labeled with 18 F in a one-step reaction with 100 mCi 18 F − at 50 °C (Figure 1). A solution of non-radioactive, 19 F-hydrogen fluoride carrier drives the reaction to completion and simultaneously buffers the reaction at pH 3 [25,26,27,28]. The conversion is confirmed by LC-MS.…”

A Murine Model for Quantitative, Real-Time Evaluation of Convection-Enhanced Delivery (RT-CED) Using an 18[F]-Positron Emitting, Fluorescent Derivative of Dasatinib

“…1 is 18 F-radiolabeled using aqueous, acid catalyzed 19 F- 18 F isotopic exchange technology (30–33). This radiochemistry can be performed with minimal radiochemistry training ([ 18 F]- 1 is successfully generated in 100% of over 10 attempted radiolabelings).…”